Non-invasive characterization of tumor response to protein kinase inhibitor therapy by PET imaging

这项建议的目的是描述肿瘤对Braf和MEK抑制剂治疗的反应以及体内和体外的肿瘤代谢。这项建议的两个目的之一是调查靶向治疗药物与甲状腺癌GLUT-1(3)表达和F-18-FDG摄取之间的相互作用。甲状腺癌是一种具有高频率Braf突变的肿瘤实体。与恶性黑色素瘤相比，甲状腺癌往往对BRAF抑制有抵抗力。耐药机制涉及刺激HER3受体的生长因子Hereglin的过度表达。我们希望在维莫拉非尼和拉帕替尼(单独或联合治疗)治疗肿瘤细胞的情况下，检测GLUT-1/GLUT-3在肿瘤细胞培养的细胞膜和胞浆中的表达。下一步，我们希望评估维莫拉非尼和拉帕替尼(单独和联合治疗)治疗几个时间点时GLUT-1(3)的表达，然后评估治疗过程中糖酵解关键酶的活性，并与GLUT-1(3)的表达进行比较。最后一步是将肿瘤细胞培养物植入小鼠体内，评估单独和联合抑制剂与FDG PET在体内的治疗效果。本建议的第二个目的是研究甲状腺癌中碘和FDG储存的反向关系，即所谓的触发器现象。最近的临床研究表明，塞鲁米替尼治疗可以显著增加转移性甲状腺癌的放射性碘摄取。我们将使用RAF抑制剂维莫拉非尼和MEK抑制剂selumetinib来研究细胞系的触发现象。低碘和高FDG储存之间是否存在联系？更有趣的是，在使用BRAF抑制剂治疗期间，细胞是否存在储存最大碘的时间段？将甲状腺肿瘤细胞系植入小鼠模型观察体内观察结果

The aim of this proposal is to characterize tumor response to braf and MEK inhibitor therapy and tumor metabolism in vitro and in vivo. One of the two aims of this proposal is to investigate the interaction between targeted therapy drugs and GLUT-1 (3) expression and F-18-FDG uptake in thyroid cancer, a tumor entity that has a high frequency of braf mutations. In contrast to malignant melanoma thyroid cancers are frequently resistant to braf inhibition. The resistance mechanism involves overexpression of the growth factor heregulin which stimulates HER3 receptors. We want to determine the GLUT-1/GLUT-3 expression in the cell membrane and in cytosol in tumor cell culture in case of therapy with vemurafenib and lapatinib (single- and combination therapy). In the next step we want to evaluate the GLUT-1 (3) expression in case of therapy with vemurafenib and lapatinib (single- and combination therapy) for several time points and then to evaluate the activity of the key enzymes of glycolysis during therapy and comparison with GLUT-1 (3) expression. The last step is to implant the tumor cell culture into mice and to evaluate the effects of the single and combination inhibitor therapy with FDG PET in vivo.The second aim of this proposal is to investigate the inverse relationship of iodine- and FDG storage, the so called flip-flop-phenomenon, in thyroid cancer. Recent clinical studies have indicated that treatment with selumetinib can dramatically increase radioiodine uptake of metastatic thyroid cancer. We will use cell lines to investigate the flip flop-phenomenon using a RAF-inhibitor vemurafenib and the MEK inhibitor selumetinib. Is there a relationship between low iodine and high FDG storage and vice versa? And more interestingly, is there a time slot in which the cells store maximum iodine during the therapy with BRAF inhibitors? Implanting the thyroid tumor cell lines into mice models to investigate observed results in vivo